Telomere attrition predominantly occurs in precursor lesions during in vivo carcinogenic process of the uterine cervix

Abstract

Although human papillomavirus (HPV) has been defined as the pathogen for cervical carcinomas, molecular events underlying the oncogenic process are unclear. As telomere dysfunction-mediated chromosomal instability and telomerase activation have been suggested as key events in carcinogenesis, we dissected the dynamic changes in telomere length, checkpoint response, and temporal profile of telomerase expression during the evolution from precursor lesions (cervical intraepithelial neoplasia, CINs) to invasive cancers of the uterine cervix in sequential samples from 16 patients. Telomeres were significantly shortened in all CIN samples and no further substantial attritions occurred in most cases with the acquisition of malignant phenotype. Very short telomeres were coupled with constitutive activation of the DNA damage response pathway (Chk2 phosphorylation) and increased cellular proliferation in those cervical specimens. Telomerase reverse transcriptase (hTERT) expression was preferably induced at advanced CINs or invasive cancers. The present finding demonstrates that excessive telomere shortening predominantly occurs in the early carcinogenesis of the uterine cervix largely prior to telomerase activation. Widespread over-erosion of telomeres or telomere dysfunction in very early stages of cervical tumorigenesis might fuel transformation processes by driving chromosomal instability.

Oncogenic Aspects of HPV Infections of the Female Genital Tract

“…The E7 effect could be important in early cancer development while E6 might play a role in later phases of oncogenesis (Moody & Laimins, 2010). This is in accordance with the observation that high levels of hTERT expression are found in advanced cervical lesions and invasive carcinomas (Zhang et al, 2004).…”

TRF2 inhibition promotes anchorage-independent growth of telomerase-positive human fibroblasts

“…On the other hand, studies on mice lacking the telomerase RNA gene demonstrate that critical telomere shortening and telomere instability can favor initial stages of cancer formation and cooperates with p53 deficiency to favor carcinogenesis Rudolph et al, 2001). In human tumorigenesis, a burst of telomere instability could occur at early stages as a consequence of an excessive telomere shortening and checkpoint inactivation (Rudolph et al, 2001;O'Sullivan et al, 2002;Chin et al, 2004;Zhang et al, 2004). This scenario is in agreement with the increased tumor susceptibility of patients carrying mutations in genes involved in chromosome stability and telomere maintenance (Callen and Surralles, 2004).…”

Transforming Growth Factor β1 Promotes Chromosomal Instability in Human Papillomavirus 16 E6E7–Infected Cervical Epithelial Cells

“…This function of E6 is expected to suppress the telomere shortening-mediated chromosomal instability. Yet the paradox is that even the premalignant cervical lesions have significantly shortened telomeres (12,13) as well as multiple chromosome abnormalities (14,15).…”